1u65

The Crystal Structure of the Complex of the Anticancer Prodrug CPT-11 with Torpedo californica Acetylcholinesterase
(see also AChE bivalent inhibitors (Part II))



CPT-11 (yellow) interacts with 13 residues of the the active-site gorge of Torpedo californica acetylcholinesterase (EC 3.1.1.7, TcAChE) from residue Trp84 at the bottom to Phe284 at its top. Nine of these residues are aromatic (Tyr70, Trp84, Tyr121, Trp279, Phe284, Phe330, Phe331, Tyr334, and His440; colored darkmagenta). The contacts made by the drug at the bottom of the gorge involve complementary surface contacts with Trp84, Tyr121, Phe331, and His440 and, especially, a stacking interaction with Phe330. The carbamate moiety of CPT-11 is located near residues Phe331 and Tyr334. Carbon C9 (shown in magenta) of the carbamate linkage in CPT-11, is 9.3 Å from Ser200 Oγ, the nucleophilic atom of the catalytic triad Ser200, His440, and Glu327. The steric clashes between CPT-11 and TcAChE residues prevents the positioning CPT-11 near the Ser200 Oγ (where hydrolysis could occur), therefore, TcAChE can not hydrolyze CPT-11.

About this Structure
1U65 is a Single protein structure of sequence from Torpedo californica. Full crystallographic information is available from OCA.

Additional Resources
For additional information, see: Alzheimer's Disease

Reference
The crystal structure of the complex of the anticancer prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11) with Torpedo californica acetylcholinesterase provides a molecular explanation for its cholinergic action., Harel M, Hyatt JL, Brumshtein B, Morton CL, Yoon KJ, Wadkins RM, Silman I, Sussman JL, Potter PM, Mol Pharmacol. 2005 Jun;67(6):1874-81. Epub 2005 Mar 16. PMID:15772291

Page seeded by OCA on Tue Jul 29 11:45:13 2008